IgD is one of five known classes of immunoglobulins. It is present on the surface of mature B cells (where it is co-expressed with IgM) but its serum levels are low. In contrast to other Ig isotypes, IgD is not secreted following antigenic stimulation of the B cells that bear it.
Although, apparently, surface IgD (sIgD) can function as a receptor for stimulation of B cells to enter the cell cycle, IgD has not been assigned a clear, specific function in immune response. At this time, more is known about what IgD does not do than what it does.
There are indications that IgD may play an important role in resistance to induction of antigen tolerance: see, Vitetta, E.S. and Uhr, J.W. Science 189:964 1975, who report that the B cells of young mice (that typically show tolerance) express only IgM, not IgD. The onset and increase of tolerance resistance parallels the ability of the B cells of the growing mouse to express IgD. The observed decrease in surface IgD of B cells subsequent to antigen stimulation is consistent with the tolerance resistance hypothesis.
Finkelman, F.D. et al. J. Immunol. 133:550, 1984 and N.Y. Acad. Sci. 399:316, 1982 have shown that administration to mice of goat anti-(mouse IgD) caused the B cells of the mice to produce significantly higher amounts of polyclonal IgGl antibodies. The authors interpreted these results as indicating the existence of nonspecific T help in the mouse system. The authors also observed an apparent suppression of antibody production when they administered high levels of goat anti-(mouse IgD).
There is evidence of the existence of T-cell sub-populations that are isotope-specific for IgA, IgE, IgG and IgM both in humans and in mice. IgA-specific T cells (T.sub.a)--but not T.sub.e, T.sub.g, or T.sub.m --have been induced by IgA-secreting plasmacytomas. These T.sub.a cells have been studied extensively but have not been found to augment humoral immune responses.
In Scand. J. Immunol. 11:377-382, 1980, 0. Sjoberg reported that a small percentage of normal human lymphocytes (0-6.5%) formed rosettes with IgD-coated latex particles. This is the earliest report known to the present inventors suggesting the existence of lymphoid cells with a receptor for IgD. However, the reported incidence of these cells does not exceed background levels for isolated peripheral blood leukocytes, which is what Sjoberg used in this study. Therefore, the results reported in this article are inconclusive. Moreover, the author does not suggest any therapeutic or other use for cells with IgD receptors.
IgD-producing plasmacytomas were discovered by Finkelman, F.D. et al. 1981 J. Immunol. 126:680, incorporated herein by reference. These plasmacytomas were induced by injecting Balb/c mice intraperitoneally with 0.5 ml of tetramethylpentadecane (pristane).
In Xue, B., et al., J. Exp. Med 159:103-113 (Jan. 1984) the authors (who include the present inventors) report the following observations for mice only:
(1) Mice bearing IgD-producing plasmacytomas or injected with IgD-containing whole ascites fluid from plasmacytoma-bearing mice exhibit enhanced antibody production upon subsequent challenge with antigen. This was observed for antibodies of both the IgM and the IgG isotype. PA1 (2) Mice injected with purified IgD, showed an increase in IgM production only.
The authors postulated that the immunoaugmenting effect was due to T cells having a receptor for IgD that were elicited following injection of IgD.
The practical significance of the work reported in this article is limited for several reasons. First, the ability of IgD-plasmacytoma or IgD-plasmacytoma ascites fluid to stimulate IgG production cannot be used for therapeutic applications in humans. Introduction of tumor cells and ascites fluid from ascites tumor bearing mice would be hazardous to the recipients.
Second, increased production of IgM is not as desirable as that of IgG antibody, especially for long term immunity. The IgG isotype has a greater affinity for the antigen and a longer half-life.
It is clear from the above discussion that a more complete understanding of the nature and role of IgD is necessary. Therefore, a broad objective of this invention is to increase this understanding and to use it to develop therapeutic methods for the management or treatment of immune system disorders.
Another object of the present invention is to provide a safe and effective method for increasing the efficiency of immunization protocols, especially in terms of other isotypes in addition to IgM, such as IgG (7S) responses.
A more specific object of the present invention is to confirm the existence of (and to provide a convenient and safe method for inducing) T cells with receptors for IgD.
Another object is to provide a convenient and safe method for inducement of T cells that are able to stimulate the immune system to produce increased amounts of IgG, and to use such T cells in the management or treatment of mammals, including humans, with depressed immune systems.
Another object is to provide a method for enhancing antibody production.
Another object is to provide a method for augmenting or restoring humoral immune response, especially in immunosuppressed or immunocompromised mammalian hosts, but also in normal vaccinated hosts.
Another object is to provide a method for augmenting or restoring humoral immune response while limiting or eliminating the infusion of exogenous substances in these hosts.
Another object is to provide a method for testing immune competence.
These and other objects of the present invention will be apparent to those skilled in the art in light of the present description, accompanying claims and appended drawings.